Cannabinoid Effects on Sleep and Pain Mechanisms in Osteoarthritis of the Knee

摘要 膝关节骨关节炎（OA）引起的慢性疼痛是导致残疾的主要原因，影响着数百万美国人。 睡眠障碍导致膝关节OA疼痛症状恶化。然而，膝关节的治疗结果 OA仍然很差。这是因为疼痛不是单一的，潜在的疼痛机制的差异会影响 治疗反应。虽然膝关节OA疼痛可能是由于组织和关节损伤（伤害性疼痛）， 通过中枢神经系统（CNS）功能障碍来增强和维持-即，伤害性疼痛不同 潜在的机制可以解释大麻素的临床试验结果不一致-活性化合物 在大麻里虽然临床试验表明大麻素可能是有用的镇痛剂和睡眠辅助剂， 这些试验是用具有滥用潜力的Δ β-四氢大麻酚（THC）和THC类似物进行的。 然而，最近的一项研究表明，大麻二酚（CBD）可以减轻膝关节炎患者的疼痛并增强其功能。 OA。CBD是无毒的，发挥镇痛和抗炎作用，也显示出对 改善睡眠。拟议的研究将研究CBD和/或THC如何影响膝关节OA的睡眠， 睡眠相关变化对疼痛的影响程度。我们的总体假设是，CBD+THC将 改善睡眠最多，其次是THC，然后是CBD，睡眠的改善将部分介导 疼痛的改善。为了验证这一假设，我们提出了三个目标，这将为我提供额外的 作为独立研究人员，统一慢性疼痛，睡眠和大麻素机制所需的培训：1） 通过帮助领导一个临床试验项目，获得临床试验实施和尖端疼痛表型分析方法方面的培训。 一项随机、双盲、2x2析因设计研究，评估疼痛集中是否预测 膝关节OA患者对CBD和THC的镇痛反应差异（母研究R 01 AT 010381）; 2）在一项研究中， 目标1内的辅助试验，通过自我报告和客观测量研究大麻素对睡眠的影响; 3)评估大麻素睡眠效应是否介导疼痛的变化，并探索睡眠与疼痛之间的相互作用。 疼痛表型鉴于疼痛集中发生在许多慢性疼痛状况中，我们在膝关节的方法 OA可能对开发非阿片类镇痛药具有广泛的意义。该奖项将在 密歇根大学（UM）在丹尼尔克劳，理查德哈里斯，史蒂芬哈特，亚历山大Tsodikov博士， 海伦·伯吉斯和大卫威廉姆斯，他们是世界知名的慢性疼痛，神经成像， 心理物理学、临床试验分析、睡眠和疼痛心理测量学。UM是理想的环境 这个奖项，因为可用的资源，包括教师谁是致力于临床疼痛研究 和指导、研究专用磁共振成像（MRI）扫描仪和最先进的疼痛测试 设备，以及充足的实验室和办公空间在慢性疼痛和疲劳研究中心。后 完成这个奖项，我将非常适合过渡到一个独立的，终身教职。

Abstract Chronic pain due to knee osteoarthritis (OA) is a large contributor to disability, affecting millions of Americans. Sleep disturbances contribute to worsened pain symptoms in knee OA. However, treatment outcomes for knee OA remain poor. This is because pain is not monolithic, and differences in underlying pain mechanisms affect treatment response. While knee OA pain can be due to tissue and joint damage (nociceptive pain), it can also be augmented and maintained by central nervous system (CNS) dysfunction - i.e., nociplastic pain. Different underlying mechanisms may explain inconsistent clinical trial results with cannabinoids - the active compounds in Cannabis sativa. While clinical trials suggest that cannabinoids may be useful analgesics and sleep-aids, these trials were done with Δ⁹-tetrahydrocannabinol (THC) and THC analogs, which have abuse potential. However, a recent study showed that cannabidiol (CBD) reduced pain and increased function in men with knee OA. CBD is non-intoxicating, exerts analgesic and anti-inflammatory effects, and also shows promise for improving sleep. The proposed studies will examine how CBD and/or THC affect sleep in knee OA, and the degree to which associated changes in sleep affect pain. Our overarching hypothesis is that CBD+THC will improve sleep the most, followed by THC, and then CBD, and that improvements in sleep will partially mediate improvements in pain. To test this hypothesis, we propose three aims that will provide me with the additional training necessary to unify chronic pain, sleep, and cannabinoid mechanisms as an independent researcher: 1) Acquire training in clinical trial conduct and cutting edge pain-phenotyping methods by helping lead a randomized, double-blinded, 2x2 factorial design study that assesses whether pain centralization predicts differential analgesic responsiveness to CBD and THC in knee OA (parent study R01AT010381); 2) In an ancillary trial within Aim 1, investigate cannabinoid effects on sleep through self-report and objective measures; 3) Assess if cannabinoid sleep effects mediate changes in pain and explore interactions between sleep and pain phenotype. Given that pain centralization occurs in many chronic pain conditions, our approach in knee OA may have broad implications for developing non-opioid analgesics. This award will take place at the University of Michigan (UM) under Drs. Daniel Clauw, Richard Harris, Steven Harte, Alexander Tsodikov, Helen Burgess, and David Williams, who are world-renowned experts in chronic pain, neuroimaging, psychophysics, clinical trial analyses, sleep, and pain psychometrics, respectively. UM is an ideal environment for this award because of the available resources, including faculty who are committed to clinical pain research and mentoring, research-devoted magnetic resonance imaging (MRI) scanners and state-of-the-art pain testing equipment, and ample laboratory and office space at the Chronic Pain and Fatigue Research Center. Upon completing this award, I will be well suited to make the transition to an independent, tenure-track faculty.